Process for hydrogenating ketones in the presence of  ru(ii) catalysts

ABSTRACT

The present invention relates to a process for hydrogenating a substrate including a carbon-heteroatom double bond, the process including the step of reacting the substrate with hydrogen gas in the presence of a hydrogenation catalyst, wherein the hydrogenation catalyst is a complex of formula (I): 
     
       
         
         
             
             
         
       
     
     R 1-10 , A and Hal are as defined in the specification. The present invention also provides processes for the preparation of the complex of formula (I) and intermediates thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 13/257,166,filed Jan. 27, 2012, which is the 35 U.S.C. 371 National Phase of PCTInternational Application No. PCT/GB2010/1050456, filed Mar. 17, 2010,which claims priority to British Patent Application No. 0904553.5, filedMar. 17, 2009; U.S. Provisional Patent Application No. 61/221,690, filedJun. 30, 2009; and British Patent Application No. 0913166.5, filed Jul.29, 2009, the disclosures of all of which are incorporated herein byreference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to a process for catalyticallyhydrogenating a substrate comprising a carbon-heteroatom double bond. Inparticular, the present invention relates to catalytically hydrogenatinga carbonyl or iminyl compound using a η⁶ arene ruthenium monosulfonateddiamine complex.

BACKGROUND OF THE INVENTION

Tethered catalysts have been used in asymmetric transfer hydrogenationreactions (see, for example. Hayes et al, J. Am. Chem. Soc., 2005, 127,7318. Cheung et al, Organic Letters, 2007, 9(22), 4659, Morris et al, J.Org. Chem., 2006, 71, 7035 and Martins et al, J. Organomet. Chem., 2008,693, 3527). The transfer hydrogenation conditions utilise formic acidand triethylamine. A hydrogenation reaction differs from a transferhydrogenation reaction in that hydrogen gas is used and not reagentssuch as formic acid and triethylamine.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a process for hydrogenating asubstrate that includes a carbon-heteroatom double bond. The processincludes the step of reacting the substrate with hydrogen gas in thepresence of a hydrogenation catalyst, wherein the hydrogenation catalystis a complex of formula (I):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, A and Hal are asdefined herein.

In another aspect, the invention provides a process for the preparationof a compound of formula (VIII):

Including the steps of:

a) converting a compound of formula (IX) into a compound of formula (X):

b) reacting the compound of formula (X) with a compound of formula (XI)in a solvent to form the compound of formula (VIII):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and A are as definedherein.

In a further aspect, the invention provides a one-pot process for thepreparation of a complex of formula (I):

including the steps of:i) treating a compound of formula (VIII) with an acid HZ, where Z is ananion

ii) reacting the acid addition salt of the compound of formula (VIII)with a Ru(Hal)_(n) complex, where Hal is a halogen and n is a numberequal to or less than the coordination number of Ru, to form a complexof formula (XIII):

iii) treating the complex of formula (XIII) with a base to form thecomplex of formula (I):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and A are as definedherein.

In yet another aspect, the invention provides a complex selected fromthe group consisting of:

In a still further aspect, the invention provides a compound, or an acidaddition salt thereof, selected from the group consisting of:

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms andConventions Used

The point of attachment of a moiety or substituent is represented by“-”. For example, —OH is attached through the oxygen atom.

“Alkyl” refers to a straight-chain, branched or cyclic saturatedhydrocarbon group. In certain embodiments, the alkyl group may have from1-20 carbon atoms, in certain embodiments from 1-15 carbon atoms, incertain embodiments, 1-10 carbon atoms. The number of carbon atoms isappropriate to the group e.g. a cycloalkyl group must have at least 3carbon atoms to form a ring. The alkyl group may be unsubstituted orsubstituted. Unless otherwise specified, the alkyl group may be attachedat any suitable carbon atom and, if substituted, may be substituted atany suitable atom. Typical alkyl groups include but are not limited tomethyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl,cyclohexyl and the like.

“Alkoxy” refers to a —O-alkyl group wherein the alkyl group is asdescribed above.

“Alkenyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon group having at least one carbon-carbon double bond. Thegroup may be in either the cis- or trans-configuration around eachdouble bond. In certain embodiments, the alkenyl group can have from2-20 carbon atoms, in certain embodiments from 2-15 carbon atoms, incertain embodiments, 2-10 carbon atoms. The alkenyl group may beunsubstituted or substituted. Unless otherwise specified, the alkenylgroup may be attached at any suitable carbon atom and, if substituted,may be substituted at any suitable atom. Examples of alkenyl groupsinclude but are not limited to ethenyl (vinyl), 2-propenyl (allyl),1-methylethenyl, 2-butenyl, 3-butenyl, cyclobut-1,3-dienyl and the like.

“Alkynyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon group having at least one carbon-carbon triple bond. Incertain embodiments, the alkynyl group can have from 2-20 carbon atoms,in certain embodiments from 2-15 carbon atoms, in certain embodiments,2-8 carbon atoms. The number of carbon atoms is appropriate to the groupe.g. a cyclic group having at least one carbon-carbon triple bond musthave a sufficient number of carbon atoms in order for the cyclic groupto be formed. The alkynyl group may be unsubstituted or substituted.Unless otherwise specified, the alkynyl group may be attached at anysuitable carbon atom and, if substituted, may be substituted at anysuitable atom. Examples of alkynyl groups include, but are not limitedto, ethynyl, prop-1-ynyl, prop-2-ynyl, 1-methylprop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl and the like.

“Aryl” refers to an aromatic carbocyclic group. The aryl group may havea single ring or multiple condensed rings. In certain embodiments, thearyl group can have from 6-20 carbon atoms, in certain embodiments from6-15 carbon atoms, in certain embodiments, 6-10 carbon atoms. The arylgroup may be unsubstituted or substituted. Unless otherwise specified,the aryl group may be attached at any suitable carbon atom and, ifsubstituted, may be substituted at any suitable atom. Examples of arylgroups include, but are not limited to, phenyl, naphthyl, anthracenyland the like.

“Aryloxy” refers to an —O-aryl group wherein the aryl group is asdescribed above.

“Hal” refers to a halogen and may be selected from the group consistingof fluorine, chlorine, bromine and iodine.

“Heteroalkyl” refers to a straight-chain, branched or cyclic saturatedhydrocarbon group wherein one or more carbon atoms are independentlyreplaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorusand/or sulfur atoms). In certain embodiments, the heteroalkyl group mayhave from 1-20 carbon atoms, in certain embodiments from 1-15 carbonatoms, in certain embodiments, 1-10 carbon atoms. The number of carbonatoms is appropriate to the group e.g. a heterocycloalkyl group musthave a sufficient number of carbon atoms together with the heteroatom toform a ring. The heteroalkyl group may be unsubstituted or substituted.Unless otherwise specified, the alkyl group may be attached at anysuitable atom and, if substituted, may be substituted at any suitableatom. Examples of heteroalkyl groups include, but are not limited to,ethers, amines, thioethers, epoxide, morpholinyl, piperadinyl,piperazinyl, thirranyl and the like.

“Heteroaryl” refers to an aromatic carbocyclic group wherein one or morecarbon atoms are independently replaced with one or more heteroatoms(e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). In certainembodiments, the heteroaryl group may have from 3-20 carbon atoms, incertain embodiments from 3-15 carbon atoms, in certain embodiments, 3-10carbon atoms. The heteroaryl group may be unsubstituted or substituted.Unless otherwise specified, the heteroaryl group may be attached at anysuitable atom and, if substituted, may be substituted at any suitableatom. Examples of heteroaryl groups include, but are not limited to,furanyl, indolyl, oxazolyl, pyrrolyl, N-methyl-pyrrolyl, pyridinyl,pyrimidinyl, pyridazinyl, thiazolyl, thiophenyl and the like.

It has been found that a substrate comprising a carbon-heteroatom doublebond may be reduced in the presence of hydrogen gas and a tethered η⁶arene ruthenium monosulfonated diamine complex. In some embodiments, thehydrogenation is asymmetric and the reduced substrate may be obtained inhigh enantiomeric excess. In some embodiments, when the substrate to behydrogenated is polyfunctionalised, it has been found that the tetheredcatalyst is resilient to the presence of the polyfunctional groups anddoes not become deactivated.

In one aspect, therefore, the present invention provides a process forhydrogenating a substrate comprising a carbon-heteroatom double bond,the process comprising the step of reacting the substrate with hydrogengas in the presence of a hydrogenation catalyst, wherein thehydrogenation catalyst is a complex of formula (I):

wherein,R₁, R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of hydrogen, optionally substituted straight, branched orcyclic C₁₋₂₀ alkyl, optionally substituted straight, branched or cyclicC₁₋₂₀ alkoxy, optionally substituted C₆₋₂₀ aryl, optionally substitutedC₆₋₂₀ aryloxy, —OH, CN, —NR₂₀R₂₁, —COOH, COOR₂₀, —CONH₂, —CONR₂₀R₂₁ and—CF₃ wherein the substituents are selected from the group consisting ofone or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branchedor cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN, —NR₃₀R₃₁,—COOR₃₀, —CONR₃₀R₃₁ and —CF₃:R₁ and R₂, R₂ and R₃, R₃ and R₄ or R₄ and R₅ together form an aromaticring composed of 6 to 10 carbon atoms which is optionally substitutedwith one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight,branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN,—NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃;R₆, R₇, R₈ and R₉ are each independently selected from the groupconsisting of hydrogen, optionally substituted straight, branched orcyclic C₁₋₂₀ alkyl, optionally substituted straight, branched or cyclicC₁₋₂₀ alkoxy, optionally substituted C₆₋₂₀ aryl and optionallysubstituted C₆₋₂₀ aryloxy wherein the substituents are selected from thegroup consisting of one or more straight, branched or cyclic C₁₋₂₀alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃, orR₆ and R₇ together with the carbon atom to which they are bound and/orR₈ and R₉ together with the carbon atom to which they are bound form anoptionally substituted C₃₋₂₀ cycloalkyl or an optionally substitutedC₂₋₂₀ cycloalkoxy, wherein the substituents are selected from the groupconsisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl,straight branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy,—OH, —CN, —NR₂₁R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃, orone of R₆ and R₇ and one of R₈ and R₉ together form an optionallysubstituted C₅₋₁₀ cycloalkyl or an optionally substituted C₅₋₁₀cycloalkoxy, wherein the substituents are independently selected fromthe group consisting of one or more straight, branched or cyclic C₁₋₂₀alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃, orR₁₀ is an optionally substituted straight, branched or cyclic C₁₋₁₀alkyl, an optionally substituted C₆₋₁₀ aryl or —NR₁₁R₁₂ wherein thesubstituents are selected from the group consisting of one or morestraight branched or cyclic C₁₋₁₀ alkyl, straight, branched or cyclicC₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, -Hal, —OH, —CN, —NR₂₀R₂₁,—COOR₂₀, —CONR₂₀R₂₁ and —CF₃;R₁₁ and R₁₂ are independently selected from the group consisting ofhydrogen, optionally substituted straight, branched or cyclic C₁₋₁₀alkyl and optionally substituted C₆₋₁₀ aryl, wherein the substituentsare selected from the group consisting of one or more straight, branchedor cyclic C₁₋₁₀ alkyl groups, straight, branched or cyclic C₁₋₁₀ alkoxy,C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and—CF₃, orR₁₁ and R₁₂ together with the nitrogen atom to which they are bound forman optionally substituted C₂₋₁₀ cycloalkyl-amino group, wherein thesubstituents are selected from the group consisting of one or morestraight, branched or cyclic C₁₋₁₀ alkyl, straight, branched or cyclicC₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀,—CONR₂₀R₂₁ and —CF₃;R₂₀ and R₂₁ are independently selected from the group consisting ofhydrogen, optionally substituted straight, branched or cyclic C₁₋₂₀alkyl, optionally substituted straight, branched or cyclic C₁₋₂₀ alkoxy,optionally substituted C₆₋₂₀ aryl, optionally substituted C₆₋₂₀ aryloxy,—OH, —CN, —NR₃₀R₃₁, —COOR₃₀, —CONR₃₀R₃₁ and —CF₃, wherein thesubstituents are selected from the group consisting of one or morestraight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclicC₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN and —CF₃;R₃₀ and R₃₁ are independently selected from the group consisting ofhydrogen, optionally substituted straight, branched or cyclic C₁₋₂₀alkyl, optionally substituted straight, branched or cyclic C₁₋₂₀ alkoxy,optionally substituted C₆₋₂₀ aryl, optionally substituted C₆₋₂₀ aryloxy,—OH, —CN and —CF₃, wherein the substituents are selected from the groupconsisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl,straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy,—OH, —CN and —CF₃;A is an optionally substituted straight- or branched-chain C₂₋₅, alkylwherein the substituents are selected from the group consisting of oneor more straight, branched or cyclic C₁₋₁₀ alkyl, straight, branched orcyclic C₁₋₁₀ alkoxy, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy, orA is a group of formula (II):

wherein p is an integer selected from 1, 2, 3 or 4;each R₄₀ is independently selected from the group consisting ofstraight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclicC₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN or —CF₃;q and r are independently integers selected from 0, 1, 2 or 3 whereinq+r=1, 2 or 3;each R₄₁ is independently selected from the group consisting ofhydrogen, straight, branched or cyclic C₁₋₂₀ alkyl, straight, branchedor cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN and —CF₃;andHal is a halogen.

The carbon atoms to which R₆, R₇, R₈ and R₉ are bound may be asymmetric.The complex of formula (I) therefore may be chiral and the hydrogenationprocess of the invention an asymmetric hydrogenation process. It isenvisaged that chiral catalysts and asymmetric hydrogenation processesare within the scope of the invention.

In one embodiment, the process is suitable for selectively hydrogenatinga carbonyl group to provide the corresponding alcohol.

A suitable substrate to be hydrogenated includes, but is not limited to,a carbonyl of formula (III):

wherein,R₅₀ and R₅₁ are each independently selected from the group consisting ofhydrogen, an optionally substituted straight, branched or cyclic C₁₋₂₀alkyl, an optionally substituted straight, branched or cyclic C₂₋₂₀alkenyl, an optionally substituted C₂₋₂₀ alkynyl, an optionallysubstituted C₆₋₂₀ aryl, an optionally substituted straight, branched orcyclic C₁₋₂₀ heteroalkyl, an optionally substituted C₃₋₂₀ heteroaryl,—NR₆₀R₆₁, —COR₆₀, —COOR₆₀, —CONR₆₀R₆₁, an optionally substituted—C₁₋₂₀-alkyl-COOR₆₀, an optionally substituted —C₁₋₂₀-alkyl-COR₆₀, anoptionally substituted —C₁₋₂₀-alkyl-CONR₆₀R₆₁, optionally substituted—C₂₋₂₀-alkynyl-C₆₋₂₀-aryl and optionally substituted—C₂₋₂₀-alkynyl-C₁₋₂₀-alkyl; orR₅₀ and R₅₁ are bound by an optionally substituted C₁₋₂₀ alkyl, anoptionally substituted C₁₋₂₀ alkoxy or an optionally substitutedC₂₋₂₀alkenyl; orR₅₀ and R₅₁ are bound to form a 5, 6 or 7 membered ring by an optionallysubstituted —(CH₂)_(t)-(ortho-C₅₋₆-aryl)-(CH₂)_(u)— chain, an optionallysubstituted —(CH₂)_(t)-(ortho-C₅₋₆-aryl)-Q-(CH₂)_(u)— chain or anoptionally substituted —(CH₂)_(t)-(ortho-C₅₋₆-heteroaryl)-(CH₂)_(u)—chain, wherein t is an integer selected from 0 or 1.u is an integer selected from 2, 3 or 4,Q is selected from the group consisting of —O—, —N— and —SO₂—,wherein the substituents are selected from the group consisting of oneor more of straight, branched or cyclic C₁₋₂₀ alkyl, straight, branchedor cyclic C₁₋₂₀alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, straight, branched orcyclic C₁₋₂₀ heteroalkyl, C₆₋₂₀ heteroaryl, straight or branchedtri-C₁₋₂₀-alkylsilyl-, -Hal, —OH, —CN, —NR₆₀R₆₁, —COR₆₀, —COOR₆₀,—CONR₆₀R₆₁ and —CF₃,wherein R₆₀ and R₆₁ are independently selected from the group consistingof hydrogen, straight branched or cyclic C₁₋₂₀ alkyl, straight branchedor cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy and —OH.

In one embodiment, when R₅₀ and R₅₁ are bound to form a 5, 6 or 7membered ring, Q is preferably —O— or —SO₂—. In another embodiment, thesubstrate to be hydrogenated may be selected from an optionallysubstituted 1-indanone, an optionally substituted 2-indanone, anoptionally substituted α-tetralone, an optionally substitutedβ-tetralone, an optionally substituted6,7,8,9-tetrahydro-5-benzocycloheptenone, an optionally substituted5,7,8,9-tetrahydro-6H-benzo[A]cyclohepten-6-one, an optionallysubstituted benzofuran-3(2H)-one, an optionally substituted 4-chromanoneand an optionally substituted 3,4-dihydro-1-benzoxepin-5(2H)-one. In oneembodiment, the substituents are selected from the group consisting ofone or more of straight branched or cyclic C₁₋₂₀ alkyl and -Hal. Inanother embodiment, the substituents are selected from methyl, ethyl,n-propyl, is-propyl, fluorine, chlorine, bromine and iodine.

In yet another embodiment, the process is suitable for selectivelyhydrogenating an iminyl group to provide the corresponding amine.

A suitable substrate to be hydrogenated includes, but is not limited to,a compound of formula (IV) or (V):

R₅₀ and R₅₁ are as described above with regard to the carbonyl offormula (III);R₅₂ is selected from the group consisting of hydrogen, an optionallysubstituted straight, branched or cyclic C₁₋₂₀ alkyl, straight, branchedor cyclic C₁₋₂₀alkoxy, an optionally substituted straight, branched orcyclic C₂₋₂₀ alkenyl, an optionally substituted C₆₋₂₀ aryl, anoptionally substituted C₆₋₂₀ aryloxy, an optionally substituted—C₁₋₂₀-alkyl-C₆₋₂₀-aryl, an optionally substituted straight, branched orcyclic C₁₋₂₀ heteroalkyl, an optionally substituted C₃₋₂₀ heteroaryl,—NR₇₀R₇₁, —COR₇₀, —COOR₇₀, —CONR₇₀R₇₁, an optionally substituted—C₁₋₂₀-alkyl-COOR₇₀, an optionally substituted —C₁₋₂₀-alkyl-COR₇₀, anoptionally substituted —C₁₋₂₀-alkyl-CONR₇₀R₇₁, —SOR₇₀, —SO₂R₇₀,—P(O)(R₇₀)₂, orR₅₂ and one of R₅₀ and R₅₁ are bound to form an optionally substitutedC₁₋₂₀-heteroalkyl group, wherein the substituents are selected from thegroup consisting of one or more straight, branched or cyclic C₁₋₂₀alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀aryloxy, straight branched or cyclic C₁₋₂₀ heteroalkyl, C₆₋₂₀heteroaryl, -Hal, —OH, —CN, —NR₇₀R₇₁—COOR₇₀, —CONR₇₀R₇₁ or —CF₃, andwherein R₇₀ and R₇₁ are independently selected from the group consistingof hydrogen, straight, branched or cyclic C₁₋₂₀ alkyl, straight,branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH,—C(O)—(C₁₋₂₀-alkyl) and —C(O)O—(C₁₋₂₀-alkyl).

When the substrate to be hydrogenated is a compound of formula (V), anysuitable anion may be present.

When R₅₀, R₅₁ and/or R₅₂ are different, the compounds of formulae (III),(IV) or (V) are prochiral and the hydrogenation catalysed by the metalcomplex of formula (I) is enantioselective. The enantiomeric excess ispreferably greater than 80% ee. In certain embodiments, the enantiomericexcess is greater than 85% ee, in certain embodiments greater than 90%ee, in certain embodiments greater than 93% ee.

The process according to the invention may be carried out either in theabsence of a solvent or in presence of a solvent. In one embodimenttherefore the process further comprises a solvent.

Preferably, the solvent comprises water, an alcohol, an aromatic solvent(such as benzene or toluene), an ether (cyclic or open chain, such astetrahydrofuran (THF) or methyl tert-butylether (MTBE)), an ester (suchas ethyl acetate) or a combination thereof. When the solvent comprisesan alcohol, preferred alcohols have boiling points at atmosphericpressure (i.e. 1.0135×10⁵ Pa) below 160° C., more preferably below 120°C. and even more preferably below 100° C. Preferred examples aremethanol, ethanol, n-propanol, isopropanol, n-butanol or combinationsthereof. More preferably, the alcohol is methanol, isopropanol or acombination thereof. Particular preference is given to methanol.

The concentration range of the complex of formula (I) may vary widely.In general, a substrate/complex ratio of about 50.000:1 to about 25:1,preferably from about 2000:1 to about 50:1, more preferably about 1000:1to about 100:1 can be achieved.

The hydrogenation process may be carried out at typical pressures ofabout 1 bar to about 100 bar. Advantageously, about 20 bar to about 85bar and, in particular, about 15 bar to about 35 bar can be used.

The hydrogenation process may be carried out at temperatures betweenabout 0° C. to about 120° C. Suitably, the process can be carried out atabout 20° C. to about 80° C. and, most suitably, at about 30° C. toabout 60° C.

The process of the present invention may further comprise a silver salt.Without wishing to be bound by theory, it is believed that the silversalt removes the halogen (Hal) from the complex of formula (I) to form aruthenium complex of formula (VI) and/or formula (VII). It is furtherbelieved that suitable silver salts are those which are more solublethan the formed AgHal.

Y is an anion from the silver salt. Preferably, the conjugate acid ofthe anion Y has a pKa in water below about 4, more preferably belowabout 2 and most preferably below about 0.

Suitable silver salts include silver perfluorinated alkanesulfonates(such as silver triflate) or silver (perfluorinatedalkanesulfonate)amides. Alternatively, silver hexafluorophosphate,silver tetrafluoroborate or silver perchlorate can be used. The silversalt may be present in any suitable mol %, for example, from about 0.2to 500 mol % to the amount of ruthenium complex used.

In another embodiment, the process of the present invention may furthercomprise a fluorinated sulfonic acid, preferablytrifluoromethanesulfonic acid. The fluorinated sulfonic acid may be usedin any suitable mol %, for example, 2 mol %.

Examples of anion Y therefore may include, but are not limited to,trifluoromethanesulphonate, tetrafluoroborate, hexafluorophosphate andperchlorate.

The ruthenium catalyst and the substrate, as well as the solvent and/oradditive if present, can be mixed in any suitable order before thehydrogen gas is applied to the reaction mixture.

The hydrogenation process may be carried out for any suitable period oftime and this period of time will depend upon the reaction conditionsunder which the hydrogenation is conducted e.g. substrate concentration,catalyst concentration, pressure, temperature and the like. Once thehydrogenation process has been determined to be complete, the productmay be isolated and purified using conventional techniques.

In one embodiment, the hydrogenation catalyst is metal complex offormula (I):

wherein R₁, R₂, R₃, R₄ and R₅ are each independently selected from thegroup consisting of hydrogen, straight branched or cyclic C₁₋₂₀ alkyl,straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy,—OH, —CN, —NR₂₀R₂₁, —COOH, COOR₂₀, —CONH₂, —CONR₂₀R₂₁ and —CF₃, inanother embodiment. R₁, R₂, R₃, R₄ and R₅ are each independentlyselected from the group consisting of hydrogen, straight- orbranched-chain C₁₋₁₀ alkyl, straight- or branched-chain C₁₋₁₀ alkoxy,C₆₋₁₀ aryl, C₆₋₁₀ aryloxy and —OH. Preferably, R₁, R₂, R₃, R₄ and R₅ areeach independently selected from the group consisting of hydrogen,straight-chain C₁₋₁₀ alkyl and branched-chain C₁₋₁₀ alkyl. Morepreferably, R₁, R₂, R₃, R₄ and R₅ are each independently selected fromthe group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl and t-butyl. Particular preference is given toR₁, R₂, R₃, R₄, and R₅ each being hydrogen.

In yet another embodiment, R₆, R₇, R₈ and R₉ are each independentlyselected from the group consisting of hydrogen, optionally substitutedstraight- or branched-chain C₁₋₁₀ alkyl, optionally substitutedstraight- or branched-chain C₁₋₁₀ alkoxy, optionally substituted C₆₋₁₀aryl and optionally substituted C₆₋₁₀ aryloxy wherein the substituentsare selected from the group consisting of straight- or branched-chainC₁₋₁₀ alkyl, straight- or branched-chain C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀aryloxy and —OH. The groups R₆, R₇, R₈ and R₉ are preferably eachindependently selected from the group consisting of hydrogen andoptionally substituted C₆₋₁₀ aryl. Preferably, R₆, R₇, R₈ and R₉ areeach independently selected from the group consisting of hydrogen orphenyl. Preferably, one of R₆ and R₇ is phenyl and the other of R₆ andR₇ is hydrogen. Preferably, one of R₈ and R₉ is phenyl and the other ofR₈ and R₉ is hydrogen.

In one embodiment, R₆, R₇, R₈ and R₉ are each hydrogen.

In another embodiment, R₆ and R₇ together with the carbon atom to whichthey are bound and/or R₈ and R₉ together with the carbon atom to whichthey are bound form an optionally substituted C₅₋₁₀ cycloalkyl or anoptionally substituted C₅₋₁₀ cycloalkoxy, wherein the substituents areselected from the group consisting of straight- or branched-chain C₁₋₁₀straight- or branched-chain C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy and—OH.

In yet another embodiment, one of R₆ and R₇ and one of R₈ and R₉together form an optionally substituted C₅₋₁₀ cycloalkyl or anoptionally substituted C₅₋₁₀ cycloalkoxy, wherein the substituents areselected from the group consisting of straight- or branched-chain C₁₋₁₀alkyl, straight- or branched-chain C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀aryloxy and —OH.

In yet another embodiment, R₁₀ is an optionally substituted straight,branched or cyclic C₁₋₁₀ alkyl, an optionally substituted C₆₋₁₀ arylwherein the substituents are selected from the group consisting of oneor more straight, branched or cyclic C₁₋₁₀ alkyl, straight, branched orcyclic C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, -Hal, —OH, —CN,—NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃. In another embodiment, thesubstituents are selected from the group consisting of one or morestraight, branched or cyclic C₁₋₁₀ alkyl, straight, branched or cyclicC₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, -Hal, or —CF₃. In anotherembodiment, R₁₀ is a straight- or branched-chain C₁₋₁₀ alkyl or a C₆₋₁₀aryl optionally substituted with one or more straight- or branched-chainC₁₋₁₀ alkyl groups. Examples of R₁₀ include, but are not limited to,p-tolyl, methyl, p-methoxyphenyl, p-chlorophenyl, trifluoromethyl,3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl,4-tert-butylphenyl, pentamethylphenyl and 2-naphthyl. Preferably, R₁₀ ismethyl or a tolyl group.

In another embodiment, R₁₀ is —NR₁₁R₁₂ wherein R₁₁ and R₁₂ areindependently selected from the group consisting of straight- orbranched-chain C₁₋₁₀ alkyl and C₆₋₁₀ aryl optionally substituted withone or more straight- or branched-chain C₁₋₁₀ alkyl groups.

In yet another embodiment, R₁₁ and R₁₂ together with the nitrogen atomto which they are bound form an optionally substituted C₅₋₁₀cycloalkyl-amino group wherein the substituents are selected from thegroup consisting of straight- or branched-chain C₁₋₁₀ alkyl, straight-or branched-chain C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy and —OH.

In one embodiment, A is an optionally substituted straight- orbranched-chain C₂₋₅alkyl, preferably an optionally substituted straight-or branched-chain C₃₋₅ alkyl, wherein the substituents are selected fromthe group consisting of straight- or branched-chain C₁₋₁₀ alkyl,straight- or branched-chain C₁₋₁₀ alkoxy, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy.Preferably, A is —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— or —(CH₂)₅—. Particularpreference is given to —(CH₂)₃— or —(CH₂)₄—.

Alternatively, A can be a group of formula (II) i.e. the —[C(R₄₁)₂]_(q)—and —[C(R₄₁)₂]_(r)— groups are ortho to each other.

wherein p is an integer selected from 1, 2, 3 or 4;each R₄₀ is independently selected from the group consisting ofstraight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclicC₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN or —CF₃;q and r are independently integers selected from 0, 1, 2 or 3 whereinq+r=1, 2 or 3: andeach R₄₁, is independently selected from the group consisting ofhydrogen, straight, branched or cyclic C₁₋₂₀ alkyl, straight, branchedor cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN or —CF₃.

In one embodiment, p is 0. The phenyl ring therefore is not substitutedby any R₄₀ groups.

In another embodiment, each R₄₁ are independently selected from thegroup consisting of hydrogen, straight-chain C₁₋₁₀ alkyl andbranched-chain C₁₋₁₀ alkyl. More preferably, each R₄₁ are eachindependently selected from the group consisting of hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.Particular preference is given to each R₄₁ being hydrogen.

Examples of A include, but are not limited to, the following:

In one embodiment, Hal is chlorine, bromine or iodine, preferablychlorine.

Preferred metal complexes of formula (I) are shown below:

Complex (B) may be prepared according to Wills et al. J. Am. Chem. Soc.,2005, 127(20), 7318. The Wills method involves five steps:

Step 1 is a Birch reduction of 3-phenyl-propanol to3-cyclohexa-1,4-dienyl-propan-1-ol. Step 2 involves a Swern oxidation of3-cyclohexa-1,4-dienyl-propan-1-ol to produce3-cyclohexa-1,4-dienyl-propionaldehyde. This stage is disadvantageous asa change in oxidation state occurs and, for the subsequent reduction,the reagent lithium aluminium hydride is used which is unsuitable forlarger scale reactions. Step 3 is a reductive amination reaction to formthe desired (R,R)-TsDPEN. However, a by-product is also formed duringthe course of the reductive amination which complicates the subsequentpurification of (R,R)-TsDPEN. Steps 4 and 5 relate to the synthesis ofthe ruthenium dimer and monomer respectively.

The inventors of the present case have overcome the above disadvantagesto provide an improved process for the preparation of the complexes offormula (I).

The present invention therefore provides a process for the preparationof a compound of formula (VIII):

-   -   comprising the steps of:    -   (a) converting a compound of formula (IX) into a compound of        formula (X):

-   -   (b) reacting the compound of formula (X) with a compound of        formula (XI) in a solvent to form the compound of formula        (VIII):

-   -   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and A are as        defined above, and X is an electrophilic group.

The process of the invention provides a process for the production of acompound of formula (VIII) which does not involve a change in oxidationstate. Moreover, a reductive amination step is not required and, assuch, the use of lithium aluminium hydride is avoided. This means thatthe process of the invention is suitable for large scale manufacturingprocedures.

Step (a) preferably comprises reacting the compound of formula (IX) witha base and a compound of formula (XII):

X-LG  (XII)

wherein LG is a leaving group.

The base is preferably an amine, for example, lutidine or triethylamine.Desirably, the reaction is carried out under an inert atmosphere (suchas nitrogen or argon). Suitably, a solvent may be used, for example, anysuitable aprotic polar solvent (such as, dichloromethane). The solventmay be anhydrous, although this is not essential.

The compound of formula (IX), the base, the solvent and the compound offormula (XII) may be added in any suitable order. In a preferred processof the invention, however, the compound of formula (IX) and the base isplaced in a reaction vessel, together with the solvent, and then thecompound of formula (XII) is added.

The compound of formula (XII) may also be present as a solution in asolvent. In this case, the solvent may be any suitable polar aproticsolvent (such as dichloromethane). The solvent may the same or differentto the solvent used to prepare the reaction mixture of the compound offormula (XII) and the base, although in a preferred embodiment of theinvention, the solvents are the same.

The compound of formula (XII) is preferably selected from the groupconsisting of trifluoromethane sulfonic anhydride, trifluoromethanesulfonic acid, methanesulfonyl chloride and p-toluenesulfonyl chloride.X therefore may be —SO₂CF₃ (for trifluoromethane sulfonic anhydride andtrifluoromethane sulfonic acid), —SO₂Me (for methanesulfonyl chloride)or —SO₂—C₆H₄-p-CH₃ (for p-toluenesulfonyl chloride). In these instances,LG may be —O—SO₂CF₃ (for trifluoromethane sulfonic anhydride), —OH (fortrifluoromethane sulfonic acid) or —Cl (for methanesulfonyl chloride orp-toluenesulfonyl chloride).

While the compound of formula (XII) is added to the reaction mixture, itis preferred that the temperature range of the reaction is maintained atone or more temperatures between about −10° C. to about 35° C. In apreferred embodiment the reaction mixture is maintained at a temperatureof less than about 5° C. In order to keep the temperature of thereaction mixture within these ranges, the compound of formula (XII)together with the solvent (if used) may be added slowly over a period oftime.

The reaction may be continued for a period of from about 30 minutes toabout 72 hours, preferably 30 minutes to about 24 hours. During thistime, the reaction temperature may be varied one or more times betweenabout −10° C. and about 25° C. If desired, on completion of thereaction, the compound of formula (X) may be separated from the reactionmixture by any appropriate method. Alternatively, the reaction mixturecomprising the compound of formula (X) may be used directly withoutisolation in step (b) of the process of the invention.

In step (b), the compound of formula (X) is reacted with the compound offormula (XI) in a solvent to form the compound of formula (VIII).

In one embodiment, the compound of formula (VIII) is the compound offormula (G):

In another embodiment, the compound of formula (VIII) is selected fromthe group consisting of:

The compounds of formulae (G), (H), (L) and (M) may be present asenantiomers or diastereoisomers. It is envisaged that enantiomers anddiastereoisomers are within the scope of the invention.

Desirably, the reaction is carried out under an inert atmosphere (suchas nitrogen or argon). Desirably, a suitable solvent is used, forexample, an aprotic polar solvent (such as dichloromethane or1,2-dimethoxy ethane). The solvent may be anhydrous, although this isnot essential. The reaction is preferably carried out at one or moretemperatures in the range of between about −10° C. to about 65° C.

Step (b) preferably further comprises a base. More preferably, the baseis an amine, for example, triethylamine.

The compound of formula (X), the compound of formula (XI), the base (ifused) and the solvent may be added in any suitable order. In oneembodiment, the compound of formula (XI) is placed in a reaction vessel,together with the solvent and the base (if used), heated if necessaryand the compound of formula (X) added, either alone or as a solution insolvent. Alternatively, the compound of formula (X) and the solvent maybe present in a reaction vessel, cooled or heated if necessary and thenthe compound of formula (XI), the base (if used) and the solvent may beadded.

The reaction may be continued for a period of from about 30 minutes toabout 24 hours. During this time, the reaction temperature may be variedone or more times between about −10° C. and about 100° C., preferablybetween about 0° C. and about 85° C. On completion of the reaction, thecompound of formula (VIII) may be separated from the reaction mixture byany appropriate method and if necessary purified.

Preferably, the process of the invention further comprises the steps of:

-   -   c) treating the compound of formula (VIII) with an acid HZ,        where Z is an anion: and    -   d) reacting the acid addition salt of the compound of        formula (VIII) with a Ru(Hal)_(n) complex, where Hal is a        halogen and n is a number equal to or less than the coordination        number of Ru, to form a complex of formula (XIII):

Step c) is preferably carried out in the presence of a solvent. Thesolvent may be any suitable solvent, for example, a polar protic solvent(such as water, methanol, ethanol, n-propanol or isopropanol), a polaraprotic solvent (such as dichloromethane or dichloroethane) or anaromatic hydrocarbon (such as toluene). Preferably, the solvent isselected from the group consisting of at least one of water, ethanol,isopropanol, dichloroethane and toluene.

Preferably, the acid HZ is selected from the group consisting ofhydrochloric acid, hydrobromic acid and hydroiodic acid. Morepreferably, the acid is hydrochloric acid. Z therefore may be achloride, bromide or iodide anion, preferably a chloride anion. In apreferred embodiment, the acid HZ is a concentrated aqueous acid.

The halogen Hal is preferably selected from the group consisting ofchlorine, bromine and iodine. In a preferred embodiment, Ru(Hal)_(n) isRuCl₃, for example, RuCl₃.H₂O or an aqueous solution of RuCl₃, includingcoordination complexes of RuCl₃ such as [RuCl₃.(H₂O)₃], [RuCl₂.(H₂O)₄]Cletc. n therefore is 3. There is a commercial advantage in using anaqueous solution of RuCl₃ in that it is much cheaper than the isolatedcomplex RuCl₃.

In one embodiment, the acid addition salt of the compound of formula(VIII) is isolated before reaction with the Ru(Hal)_(n) complex.

In another embodiment, the acid addition salt of the compound of formula(VIII) is prepared in situ before reaction with the Ru(Hal)_(n) complex.In this case, it is desirable that the solution of the acid additionsalt of the compound of formula (VIII) is warmed to one or moretemperatures in the range from about 50° C. to about 80° C. and morepreferably about 50° C. to about 75° C. before the addition of theRu(Hal)_(n) complex.

The Ru(Hal)_(n) complex may added as a solution or a suspension in asolvent. The solvent may be any suitable solvent, for example, a polarprotic solvent (such as water, methanol, ethanol, n-propanol orisopropanol), a polar aprotic solvent (such as dichloromethane ordichloroethane) or an aromatic hydrocarbon (such as toluene).Preferably, the solvent is selected from the group consisting of atleast one of water, ethanol, isopropanol, dichloroethane and toluene.The solvent or solvent mixture may be the same or different to thesolvent used in step c).

The reaction is preferably carried out at a temperature in the rangefrom about 50° C. to about 100° C. and more preferably about 50° C. toabout 85° C. It is preferred that the reaction temperature is maintainedbelow the decomposition temperatures of the RuL_(n) and the complex offormula (XIII). As such, when it is known that RuL_(n) or the complex offormula (XIII) decompose within the temperature ranges given above, thereaction temperature should be maintained below the decompositiontemperatures.

Preferably, the compound of formula (VIII) is present in the reactionmixture in stoichiometric excess. Preferably the amount of the compoundof formula (VIII) in the reaction mixture is calculated to provide amolar excess of at least 5% over the amount required for thestoichiometric reaction, more preferably an excess of at least 9%.

The reactants may be added in any suitable order, but in a preferredprocess of the invention the diluted aqueous solution of the Ru(Hal)_(n)complex is added to the solution of the acid addition salt of thecompound of formula (VIII). It is desirable that the diluted aqueoussolution of the Ru(Hal)_(n) complex is added to the solution of the acidaddition salt of the compound of formula (VIII) slowly in order to avoidan uncontrollable exotherm.

The reaction may be carried out for a period from about 30 minutes toabout 24 hours. On completion, the complex of formula (XIII) may beisolated from the reaction mixture. In this case, the complex isseparated by any appropriate method which is dependent on the physicalform of the product. Purification of the complex of formula (XIII) isnot normally required, although if necessary it is possible to purifythe complex using conventional procedures.

Alternatively, it may be desirable to prepare the complex of formula(XIII) in situ.

Preferably, the present invention further comprises the step of treatingthe complex of formula (XIII) with a base to form the complex of formula(I):

The complex of formula (XIII) is preferably present in a solvent. Thesolvent may be any suitable solvent, for example, a polar protic solvent(such as methanol, ethanol, n-propanol or isopropanol), a polar aproticsolvent (such as dichloromethane or dichloroethane) or an aromatichydrocarbon (such as toluene). Preferably, the solvent is selected fromthe group consisting of at least one of ethanol, isopropanol,dichloromethane, dichloroethane and toluene. The solvent or solventmixture may be the same or different to the solvents used in step c)and/or step d).

The base is preferably an amine, for example, triethylamine orN,N-diisopropylamine. In a preferred embodiment, the base isN,N-diisopropylamine.

The reaction may be continued for a period of from about 20 minutes toabout 24 hours. During this time, the reaction temperature may be variedone or more times between about −10° C. and about 100° C. preferablybetween about 0° C. and about 85° C. It is preferred that the reactiontemperature is maintained below the decomposition temperature of thecomplex of formula (I). As such, when it is known that the complex offormula (I) decomposes within the temperature ranges given above, thereaction temperature should be maintained below the decompositiontemperature.

On completion of the reaction, the compound of formula (VIII) may beseparated from the reaction mixture by any appropriate method which isdependent on the physical form of the product. In particular, solidcomplexes may be recovered by filtering, decanting or centrifuging. Ifpurification is necessary, the complexes may be obtained in high purityby conventional methods.

In another aspect, the present invention provides a one-pot process forthe preparation of a complex of formula (I):

-   -   comprising the steps of:    -   i) treating a compound of formula (VIII) with an acid HZ, where        Z is an anion

-   -   ii) reacting the acid addition salt of the compound of        formula (VIII) with a Ru(Hal)_(n) complex, where Hal is a        halogen and n is a number equal to or less than the coordination        number of Ru, to form a complex of formula (XIII):

-   -   iii) treating the complex of formula (XIII) with a base to form        the complex of formula (I):

-   -   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and A are as        defined above, and wherein the acid addition salt of the        compound of formula (VIII) and the complex of formula (XIII) are        prepared in situ.

In yet another aspect, the present invention provides a complex offormula (I) or formula (XIII):

-   -   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀, A, Hal and Z        are as defined above.    -   provided that the complex of formula (I) is not:

-   -   and the complex of formula (XIII) is not:

Preferably, the complex of formula (I) selected from the groupconsisting of:

In another aspect, the present invention provides a compound of formula(VIII), or an acid addition salt thereof.

-   -   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and A are as        defined above, provided that the compound of formula (VIII) is        not:

-   -    or the hydrogen chloride salt thereof,    -   or

Preferably, the compound of formula (VIII), or an acid addition saltthereof, is selected from the group consisting of:

The invention is further illustrated by reference to the followingnon-limiting Examples.

Example 1 Birch reduction of 3-phenyl-propanol

Ammonia is condensed in a round-bottomed flack with four necks(thermometer, a cold finger connected to ammonia lecture bottle, argoninlet with silicone oil bubbler, inlet closed with a stopper). The coldfinger is cooled with dry ice and the flask is cooled in a dry ice-EtOHbath. When between 50 and 100 mL of ammonia have been collected (a slowflow of argon is maintained throughout the reaction), 3-phenyl-propanol(5.0 g, MW 136.2, 36.7 mmol) in EtOH (20 mL) are added. Portions oflithium wire are added (˜1.0 g) so that the reaction is maintained darkgreen. After 2 hours at −78° C. the reaction is allowed to warm up toroom temperature and the ammonia to evaporate. The reaction is thenquenched with a saturated solution of ammonium chloride (200 mL) andextracted with dichloromethane (2×200 mL). The combined dichloromethanefractions are washed with 200 mL of HCl 2N, then dried over Na₂SO₄. Thesolvent is removed at the rotavapor to give a clear colourless oil (4.77g, 95% yield). Purity is determined by ¹H NMR.

Example 2 Synthesis of tethered (R,R)-TsDPEN

A solution of 3-(1,4-cyclohexadien-1-yl)-1-propanol (MW: 138.21; 22.1 g,0.16 mol, 1.6 eq.) and 2,6-lutidine (MW: 107.16, d: 0.92 g/ml; 24.5 ml,0.21 mol, 2.10 eq.) in anhydrous CH₂Cl₂ (500 ml) was cooled to 0° C.under N₂. A solution of triflic anhydride (MW: 281.14, d: 1.67/; 29.1ml, 0.17 mol, 1.7 eq.) in anhydrous CH₂Cl₂ (100 ml) was added slowly,keeping the internal temperature below 5° C. The resulting ambersolution was stirred for 30 min at 0° C. 60 min at room temperature, andcooled back to 0° C. A solution of (R,R)-TsDPEN (MW: 366.48; 36.6 g,0.10 mol) and triethylamine (MW: 101.19, d: 0.726; 33.5 ml, 0.24 mol,2.4 eq.) in anhydrous CH₂Cl₂ (100 ml) was added slowly, keeping theinternal temperature below 5° C. At the end of the addition, stirringwas continued for 30 min at 0° C. and then at room temperature overnight (17.5 h). The reaction mixture was diluted with CH₂Cl₂ (500 ml),washed with sat. aq. NaHCO₃ (2×500 ml, 1×250 ml), water (2×300 ml),brine (250 ml), dried over MgSO₄, and concentrated under reducedpressure to give a highly viscous, amber oil. Ethanol (250 ml) wasadded, and the mixture was stirred until a solid formed. Additionalethanol (450 ml) was added, and the mixture was heated to 70° C. until aclear solution was obtained, which was allowed to cool to roomtemperature over night. The thick suspension (solvent not visible,voluminous product) was filtered, and the off-white precipitate waswashed with ethanol, hexane, and dried under high vacuum. Yield: 34.10 g(70%), NMR purity >98% (¹H NMR).

Example 3 Synthesis of tethered (S,S)-MsDPEN

A solution of 3-(1,4-cyclohexadien-1-yl)-1-propanol (MW: 138.21; 8.3 g,60.0 mmol, 1.20 eq.) and 2,6-lutidine (MW: 107.16, d: 0.92 g/ml; 8.3 ml,70.0 mmol, 1.40 eq.) in anhydrous CH₂Cl₂ (250 ml) was cooled to 0° C.under N₂. A solution of triflic anhydride (MW: 281.14, d: 1.677; 10.7ml, 62.5 mmol, 1.25 eq.) in anhydrous CH₂Cl₂ (40 ml) was added slowly,keeping the internal temperature below 5° C. The resulting ambersolution was stirred for 30 min at 0° C., 90 min at room temperature,and cooled back to 0° C. A solution of (S,S)-MsDPEN (MW: 290.39; 14.52g, 50.0 mmol) and triethylamine (MW: 101.19, d: 0.726; 11.2 ml, 80.0mmol, 1.6 eq.) in anhydrous CH₂Cl₂ (90 ml) was added slowly, keeping theinternal temperature below 5° C. At the end of the addition, stirringwas continued for 30 min at 0° C. and then at room temperature overnight (20.5 h). The reaction mixture was diluted with CH₂Cl₂ (totalvolume: ca. 500 ml), washed with sat. aq. NaHCO₃ (2×250 ml, 1×150 ml),water (2×200 ml), brine (200 ml), dried over MgSO₄, and concentratedunder reduced pressure to give a highly viscous, amber oil (26.5 g). Thecrude product was filtered through a layer of silica gel (7 cm thick, 9cm in diameter) with EtOAc/hexane 2/1 as eluent. The product wasobtained with the first two fractions (200 ml each) but still containedan impurity, which eluted first (TLC in EtOAc, R_(t)(impurity): 0.76,R_(f)(tethered MsDPEN): 0.66; visualised with UV @254 nm or with basicKMnO₄). Evaporation of the solvents under reduced pressure yielded thecrude product as a yellow-to-orange oil, which slowly solidified (20.2g).

The solid was dissolved in MTBE (500 ml) and the solution was cooled toca. 0° C. A 1.25 M solution of HCl in MeOH (120 ml, 150 mmol) was addedwith vigorous stirring. After 45 min at 0° C. the thick suspension wasfiltered, the solid was washed with MTBE, and dried under high vacuum.Yield: 17.13 g (77%), NMR purity >98% (¹H NMR).

A second batch of product was obtained by working up the mother liquor:The combined filtrate and washings were evaporated to dryness underreduced pressure until a solid was obtained, which was triturated withethyl acetate (40 ml) at 70° C. for 1 hour. After cooling to roomtemperature, the mixture was filtered and the filter cake was washedwith EtOAc. The off-white solid was then dried under high vacuum. Yield:1.66 g (7%), NMR purity >98% (H NMR).

Example 4 Synthesis of Ts-DPEN Ru dimer

Procedure 1.

To a stirred suspension of (R,R)-tethered-diamine (11.68 g, 24 mmol) inEtOH (500 mL) was added concentrated HCl (3 mL, 37%, 36 mmol) at 60° C.and solution stirred for 30 minutes. The solution was then heated to 75°C. and to this was added RuCl₃ in H₂O (Assay 19.23% in Ru, 6.46 mL, 20mmol) in EtOH (50 mL) added dropwise over 1 hour. The solution was thenstirred at 75° C. overnight. The solution was then cooled, hexane (600mL) added with vigorous stirring and solution filtered. The solidsobtained were then washed with hexane, collected and dried under highvacuum to give a light brown solid (˜15 g, carried forward). Theisolated product was shown to be >95% pure by ¹H NMR (CDCl₃). No furtherpurification was attempted and this material was carried forward to thenext step.

Procedure 2.

To a stirred suspension of (R,R)-diamine (2.9 g, 6 mmol) in DCE (20 mL)was added HCl (3 mL, 37%, 36 mmol) at 50° C. and solution stirred for 30minutes. The resulting suspension was then heated to 75° C. and to thiswas added RuCl₃ in H₂O (Assay 19.23% in Ru, 1.62 mL, 5 mmol) in IPA (20mL) added dropwise over 1 hour. The solution was then stirred at 75° C.overnight. The solution was then cooled, hexane (100 mL) added withvigorous stirring and solution filtered. The solids obtained were thenwashed with hexane, collected and dried under high vacuum to give alight brown solid (˜6 g, carried forward). The dimer was isolated as acrude solid and shown to be >90% pure by ¹H NMR (CDCl₃).

Procedure 3.

To a stirred suspension of (R,R)-diamine (2.9 g, 6 mmol) in Toluene (20mL) was added HCl (3 mL 37%, 36 mmol) at 50° C. and the solution wasstirred for 30 minutes. The resulting suspension was then heated to 75°C. and to this was added RuCl₃ in H₂O (Assay 19.23% in Ru, 1.62 mL 5mmol) in IPA (20 mL) dropwise over 1 hour. The solution was then stirredat 75° C. overnight. The solution was then cooled, hexane (100 mL) addedwith vigorous stirring and solution filtered. The solids obtained werethen washed with hexane, collected and dried under high vacuum to give alight brown solid (˜6 g, carried forward). The dimer was isolated as acrude solid and shown to be >90% pure by ¹H NMR (CDCl₃).

Example 5 Synthesis of [Ts-teth-DPEN Ru Cl] (monomer)

Procedure 1.

To a stirred solution of the (R,R)-dimer (carried forward, ˜20 mmol) inDCM (300 mL) at 0° C. was added N,N-diisopropylethylamine (20.9 mL, 120mmol) and solution stirred at room temperature for 1 hour. The solutionwas then filtered over celite, IPA (300 mL) added and the DCM removed byrotary evaporation. The resulting suspension was then filtered and solidcollected as a dark orange solid. The solid was then further dried underhigh vacuum over night to give a fine orange powder (10.6 g, 83%).Isolated product was shown to be >95% pure by ¹H NMR (CDCl₃).

Procedure 2.

To a stirred solution of the (R,R)-dimer (14 g, ˜20 mmol) in IPA (1 L)at 50° C. was added N,N-diisopropylethylamine (20.9 mL, 120 mmol) andsolution stirred at 85° C. for 2 hours. The solution was then cooled,evaporated to a third of its original volume and then filtered to give adark orange solid. The solid was then further dried under high vacuumover night to give a fine orange powder (8.5 g, 67%). Isolated productwas shown to be >95% pure by ¹H NMR (CDCl₃).

Example 6 Synthesis of [Ts-teth-DPEN Ru Cl] one-pot

Procedure 1.

To a stirred suspension of (R,R)-diamine (2.9 g, 6 mmol) in Toluene (20mL) was added HCl (0.75 mL, 37%, 9 mmol) at 50° C. and solution stirredfor 30 minutes. The resulting suspension was then heated to 75° C. andto this was added RuCl₃ in H₂O (Assay 19.23% in Ru, 1.62 mL, 5 mmol) inIPA (10 mL) added dropwise over 1 hour. The solution was then stirred at75° C. overnight (16 h). The solution was then cooled to 0° C., toluene(30 mL) added and N,N-diisopropylethylamine (4.35 mL, 25 mmol) addeddropwise with stirring. The solution was then allowed to warm to roomtemperature and then heated to 80° C. for 30 mins. The solution was thencooled, diluted with DCM (50 mL), filtered over neutral alumina (1g/mmol) and pad washed with further portions of DCM (2×20 mL). Thefiltrate was evaporated to remove the DCM/toluene, IPA (50 mL) added andsolution stirred at room temperature for 1 h. The resulting slurry wasthen filtered to give an orange solid, which was dried under high vacuumfor 2 hours (2 g, 63%). No exotherm was observed at this scale, but careshould be taken, as this could be possible at larger scale. After theinitial heating phase a thick precipitate formed which resulted in thestirring of the solution failing. Addition of the toluene and Hunigsbase however resulted in re-dissolution of the solids as the monomerformation proceeded. Isolated product was shown to be >95% pure by ¹HNMR (CDCl₃).

Procedure 2.

To a stirred suspension of (S,S)-diamine (14.5 g, 30 mmol) in Toluene(100 mL) under nitrogen was added HCl (3.75 mL 37%, 45 mmol) at 50° C.and solution stirred for 30 minutes. The resulting suspension was thenheated to 75° C. and to this was added RuCl₃ in H₂O (Assay 19.23% in Ru,8.1 mL 25 mmol) in IPA (50 mL) added dropwise over 1 hour. The solutionwas then stirred at 75° C. overnight (16 h). The solution was thencooled to 0° C., DCM (100 mL) added and N,N-diisopropylethylamine (21.75mL, 125 mmol) added dropwise with stirring. The solution was thenallowed to warm to room temperature and then stirred for 2 h. Thesolution was then filtered over neutral alumina (1 g/mmol) and padwashed with further portions of 10% IPA/DCM (2×50 mL). The filtrate wasevaporated to remove the DCM/toluene, IPA (200 mL) added and solutionstirred at room temperature for 2 h. The resulting slurry was thenfiltered to give an orange solid, which was washed with cold IPA (30 mL)and dried under high vacuum for 2 hours (12.3 g, 77%). After the initialheating phase a thick precipitate formed which resulted in the stirringof the solution failing. Addition of the DCM and Hunigs base howeverresulted in re-dissolution of the solids as the monomer formationproceeded. Crude Isolated product was shown to be >95% pure by ¹H NMR(CDCl₃). Further purification can be undertaken by dissolution with DCM(100 mL) and IPA (100 mL), followed by removal of the DCM by rotaryevaporation. The resulting slurry could then be filtered as before andsolids dried to give pure material.

Example 7 Synthesis of [Ms-teth-DPEN Ru Cl] one-pot

Procedure 1.

To a stirred suspension of (S,S)-diamine.HCl (2.67 g, 6 mmol) in Toluene(20 mL) at 75° C. under nitrogen was added RuCl₃ in H₂O (Assay 19.23% inRu, 1.62 mL, 5 mmol) in IPA (10 mL) dropwise over 1 hour. The solutionwas then stirred at 75° C. overnight (16 h). The solution was thencooled to 0° C. DCM (30 mL) added and N,N-diisopropylethylamine (4.35mL, 25 mmol) added dropwise with stirring. The solution was then allowedto warm to room temperature and stirred for 2 h. The solution was thendiluted with DCM (50 mL), filtered over neutral alumina (1 g/mmol) andpad washed with further portions of DCM (2×20 mL). The filtrate wasevaporated to remove DCM/toluene, IPA (50 mL) added and solution stirredat room temperature for 1 h. The resulting slurry was then filtered togive an orange solid, which was dried under high vacuum for 2 hours (1.8g, 64%); After the initial heating phase a thick precipitate was notobserved in comparison to the Ts example. Isolated product was shown tobe >95% pure by ¹H NMR (CDCl₃).

Procedure 2.

To a stirred suspension of (R,R)-diamine.HCl (8.03 g, 18 mmol) inToluene (60 mL) at 75° C. under nitrogen was added RuCl₃ in H₂O (Assay19.23% in Ru, 4.86 mL, 15 mmol) in IPA (30 mL) dropwise over 1 hour. Thesolution was then stirred at 75° C. overnight (16 h). The solution wasthen cooled to 0° C., DCM (100 mL) added and N,N-diisopropylethylamine(15.66 mL, 90 mmol) added dropwise with stirring. The solution was thenallowed to warm to room temperature and stirred for 2 h. The solutionwas then filtered over neutral alumina (1 g/mmol) and pad washed withfurther portions of 10% IPA/DCM (2×50 mL). The filtrate was evaporatedto remove the DCM/toluene. IPA (200 mL) added and solution stirred atroom temperature for 2 h. The resulting slurry was then filtered to givean orange solid, which was washed with cold IPA (30 mL) and dried underhigh vacuum for 2 hours (5.0 g, 60%); After the initial heating phase athick precipitate was not observed in comparison to the Ts example.Crude Isolated product was shown to be >95% pure by ¹H NMR (CDCl₃).Further purification could be undertaken by dissolution with DCM (100mL) and IPA (100 mL), followed by removal of the DCM by rotaryevaporation. The resulting slurry could then be filtered as before andsolids dried to give pure material.

Example 8 Synthesis of Achiral Tethered Catalysts

Synthesis of the Ligand (Steps 1 and 2)

To a stirred solution of 3-(1,4-cyclohexadien-1-yl)-1-propanol (MW:138.21; 1.21 g, 9.18 mmol) in 25 mL of DCM 2.7 mL of NEt₃ (19.28 mmol)was added and cooled to 0° C. A solution of methane sulfonyl chloride(1.1 mL, 13.8 mmol) was added over a period of 20 min by keeping theinternal temperature below 5° C. After 30 min the reaction mixture wasallowed to warm up to RT and stirred overnight. The reaction wasquenched with saturated NaHCO₃ solution. The reaction was worked up withwater, brine and dried over Na₂SO₄. The mesylate derivative (96% yield)was isolated was carried forward to the next step. To a stirred solutionof monotosylated ethylenediamine (1.98 g, 9.25 mmol) in 20 mL of1,2-dimethoxy ethane and NEt₃ (2.7 mL, 19.43 mmol) at 60° C. a solutionof the mesylate derivative in 10 mL of DME was added slowly over aperiod of 5 min. Then the solution was heated to 80° C. and stirredovernight. The reaction was quenched with saturated NaHCO₃ solution. Thereaction was worked up with water, brine and dried over Na₂SO₄. Thedesired ligand was isolated by column chromatography with EtOAc aseluent (R_(f) value 0.1 in EtOAc; visualised with UV @254 nm or withbasic KMnO₄). Isolated yield of the ligand was 1.0 g (33% based on thestarting alcohol). ¹H NMR: (300 MHz, CDCl₃) 7.77-7.73 (2H, m, ArH),7.32-7.27 (2H, m, ArH), 5.71 (2H, br s, CH═CH), 5.34 (2H, br s, ═CH),3.04-3.00 (2H, m, CH₂NH), 2.82-2.73 (2H, m, CH₂NH), 2.72-2.68 (2H, m,—CH₂—C═ or ═CH—CH₂—CH═), 2.56-2.51 (4H, m, —CH₂—C═ or ═CH—CH₂—CH═), 2.42(3H, s, CH₃), 1.95-1.90 (2H, m, —NH—CH₂—), 1.53-1.48 (2H, m,—CH₂—CH₂—CH₂).

Synthesis of Dimer (Step 3)

To a stirred solution of tethered ethylenediamine ligand (MW: 334.17,0.270 g, 0.808 mmol) in EtOH (15 mL) was added concentrated HCl (0.12mL, 35%, 1.212 mmol) at 0° C. The solution was heated at 60° C. for 30minutes. After this the solution was heated to 75° C. and a solution ofRuCl₃ (0.110 g, 0.533 mmol) in EtOH (15 mL) and water (0.5 mL) addeddropwise over 20 min. The solution was then stirred at 75° C. overnight.The solution was then cooled, hexane (60 mL) added with vigorousstirring and filtered. The solids obtained were then washed with hexane,collected and dried under high vacuum to give a dark brown solid (0.006g). The filtrate was concentrated to give orange powder (0.040 g). Boththese solids were combined for the next reaction. The isolated productwas shown to be >95% pure by ¹H NMR: ¹H NMR (300 MHz, DMSO-d6) 8.50 (2H,br s, NH₂), 7.82 (2H, br s, NH), 7.71-7.68 (2H, m, ArH), 7.44-7.42 (2H,m, ArH), 6.02 (2H, br s, Ru—ArH), 5.79 (3H, br s, Ru—ArH), 2.98 (5 or6H, br s, CH₂), 2.30 (3H, s, CH₃), 1.92 (2H, br s, —CH₂—).

Synthesis of Monomer (Step 4)

To a stirred solution of the dimer (MW: 1081.80, 0.238 g, 0.220 mmol) inDCM (50 mL) at 0° C. was added N,N-diisopropylethylamine (3.0 mL, 1.696mmol) and the solution was stirred at room temperature for 2 hours. Thesolution was then filtered over celite and the DCM was removed by rotaryevaporation. EtOH was added to the resulting paste and stored in thefreezer for 3 hours and the cold solution was filtered and an orangeprecipitate was collected. The dark precipitate was washed with furtherportions of cold EtOH. The desired ruthenium complex was isolated bycolumn chromatography with EtOAc (R_(f) value 0.2 in EtOAc; visualisedwith UV @254 nm and phosphomolybdic acid). ¹H NMR (300 MHz, DMSO-d6)7.68 (1H, br s, NH), 7.82 7.59 (2H, d, ArH), 7.13 (2H, d, ArH), 5.91(1H, m, Ru—ArH), 5.79-5.71 (2H, m, Ru—ArH), 5.26-5.20 (2H, m, Ru—ArH),2.29 (3H, s, CH₃).

Example 9 Hydrogenation of Acetophenone Using Tethered-Ts/MsDPENRuClCatalysts and Optional Additives

Experimental Procedure: Ru catalyst (1.2 mg, 1.9×10⁶ mol) and silversalt (3.8×10⁻⁶ mol) (if present) were weighed into a glass reactiontube. MeOH (3 mL) added, followed by acetophenone. The vessel was placedin a Biotage Endeavour and flushed with nitrogen, then hydrogen gas. Thereaction was heated to 50° C. under 30 bar (450 PSI) H₂ for 16 hours andanalysed by TLC and GC.

See Table 1 for the results of the hydrogenation experiments.

Example 10 Hydrogenation of acetophenone with [(R,R)-Ts-teth-DPEN Ru Cl]and [(S,S)-Ts-teth-DPEN Ru Cl]

Experimental Procedure: Ru catalyst (0.005 mol) weighed into a glassreaction tube. The vials were placed in a Biotage Endeavour and flushedwith nitrogen. Acetophenone was added, followed by MeOH. The reactionwas purged with hydrogen gas, heated and pressurised. The reaction washeated and pressurised with H₂ for 16 hours and analysed by GC.

See Table 2 for the results of the hydrogenation of acetophenone with[(R,R)-Ts-teth-DPEN Ru Cl]

See Table 3 for the results of the hydrogenation of acetophenone with[(S,S)-Ts-teth-DPEN Ru Cl]

Example 11 Hydrogenation of Acetophenone Comparative Experiments in MeOH

Experimental Procedure: Ru catalyst weighed into a glass reaction tube.The vials were placed in a Biotage Endeavour and flushed with nitrogen.Acetophenone was added, followed by MeOH (total reaction volume: 4 mL).The reaction was purged with hydrogen gas, heated and pressurised. Thereaction was heated under 30 bar (435 psi) H₂ for 16 hours and analysedby and GC.

See Table 4 for the results of the comparative experiments.

As can be seen, the non-tethered catalyst is less active than thetethered catalyst when the catalyst loading was reduced to S/C 1000/1.

Example 12 Hydrogenation of Acetophenone with Tethered TsEn-Ru Catalyst

See Table 5 for the results of the hydrogenation of acetophenone withthe tethered TsEn-Ru catalyst.

TABLE 1 Conver- Substrate/ AgX sion Ee Expt Catalyst Catalyst (mol %)(%)^(a) (%)^(a) 1 Ts-DPEN Teth RuCl 100/1 — 70 94 2 Ts-DPEN Teth RuCl100/1 AgOTf (2)^(b) 84 90 3 Ts-DPEN Teth RuCl 100/1 AgPF₆ (2) 16 87 4Ts-DPEN Teth RuCl 100/1 AgBF₄ (2) 69 92 5 Ts-DPEN Teth RuCl 200/1 AgOTf(1) 80 94 6 Ts-DPEN Teth RuCl 400/1 AgOTf (0.5) 63 92 7 Ts-DPEN TethRuCl 100/1 TfOH (2) 24 90 8 Ms-DPEN Teth RuCl 100/1 — 38 82 9 Ms-DPENTeth RuCl 100/1 AgOTf (2) 94 92 10 Ms-DPEN Teth RuCl 100/1 AgPF₆ (2) 4192 11 Ms-DPEN Teth RuCl 100/1 AgBF₄ (2) 25 84 ^(a)Determined by GC.^(b)—OTf is trimethanesulfonate.

TABLE 2 hydrogenation of acetophenone with [(R,R)-Ts-teth-DPEN Ru Cl]Scale Alcohol ee Expt. S/C Solv. [S] Press. Temp. Time (%)^(a) (%)^(a)12 200/1 MeOH 1 mmol [0.5M] 30 bar 50° C. 16 h >99%  95% (R) 13 250/1MeOH 1 mmol [0.4M] 30 bar 50° C. 16 h >99% 94.5% (R) 14 500/1 MeOH 2mmol [0.5M] 30 bar 50° C. 16 h   67% 92.5% (R) 15 500/1 MeOH 2 mmol[0.5M] 30 bar 60° C. 16 h >99% 94.5% (R) 16 500/1 MeOH 10 mmol [1M]   15bar 60° C. 24 h   97% 91.5% (R) ^(a)Determined by GC (ChromPackCP-Chirasil-Dex-CB 25 m × 0.25 mm × 0.25 μm. 100° C. for 10 min, then to200° C. @ 10° C./min, 10 psi He flow, injector: 200° C.; detector (FID):210° C.

TABLE 3 hydrogenation of acetophenone with [(S,S)-Ts-teth-DPEN Ru Cl]Scale Alcohol ee Expt. S/C Solv. [S] Press. Temp. Time (%)^(a) (%)^(a)17 100/1 MeOH 2 mmol [0.5M] 30 bar 40° C. 16 h 100% 94% (S) 18 250/1MeOH 2 mmol [0.5M] 30 bar 50° C. 16 h 100% 94% (S) 19 500/1 MeOH 2 mmol[0.5M] 30 bar 60° C. 16 h 100% 93.5% (S)  20 1000/1  MeOH 2 mmol [0.5M]30 bar 60° C. 16 h 100% 93% (S) 21 2000/1  MeOH 4 mmol [1M]  30 bar 60°C. 16 h  49% 93% (S) ^(a)Determined by GC (ChromPack CP-Chirasil-Dex-CB25 m × 0.25 mm × 0.25 μm. 100° C. for 10 min, then to 200° C. @ 10°C./min, 10 psi He flow, injector: 200° C.; detector (FID): 210° C.

TABLE 4 hydrogenation of acetophenone: comparative experiments in MeOHScale Alcohol ee Expt. S/C Catalyst [S] Press. Temp. Time (%)^(a)(%)^(a) 22 100/1 [(S,S)Ts-teth- 2 mmol [0.5M] 30 bar 40° C. 16 h >99%94% (S) DPEN Ru Cl] 22 100/1 [(S,S)-TsDPEN 2 mmol [0.5M] 30 bar 40° C.16 h >99% 92% (S) (Comparative) Ru(p-cym)Cl] 23 500/1 [(S,S)Ts-teth- 2mmol [0.5M] 30 bar 60° C. 16 h >99% 93.5% (S)  DPEN Ru Cl] 23 500/1[(S,S)-TsDPEN 2 mmol [0.5M] 30 bar 60° C. 16 h >99% 93.5% (S) (Comparative) Ru(p-cym)Cl] 24 1000/1  [(S,S)Ts-teth- 2 mmol [0.5M] 30bar 60° C. 16 h >99% 94% (S) DPEN Ru Cl] 24 1000/1  [(S,S)-TsDPEN 2 mmol[0.5M] 30 bar 60° C. 16 h   77% 93% (S) (Comparative) Ru(p-cym)Cl]^(a)Determined by GC (ChromPack CP-Chirasil-Dex-CB 25 m × 0.25 mm × 0.25μm. 100° C. for 10 min, then to 200° C. @ 10° C./min, 10 psi He flow,injector: 200° C.; cetector (FID): 210° C.

TABLE 5 Hydrogenation of acetophenone with Ru catalyst A.^(a) S/CTemperature Expt. Catalyst (molar ratio) (° C.) Conv. to 2 (%) 25[Ts-teth-EN Ru Cl] 100 30 100 26 [Ts-teth-EN Ru Cl] 250 40 100 27[Ts-teth-EN Ru Cl] 1000 50 50 ^(a)Reaction conditions: Endeavor catalystscreening system; Catalyst, 1 (3.0 mmol), MeOI− (1.0 ml/mmol), 31 barH₂, 16 h. ^(b)Analysed by GC (Column: CP-Sil 5 CB, 30 m, 0.25 mm, 1 μm).

1-17. (canceled)
 18. A complex selected from the group consisting of:


19. A compound, or an acid addition salt thereof, selected from the group consisting of:


20. A complex of formula (I):

wherein, R₁, R₂, R₃, R₄ and R₅ are each independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C₁₋₂₀ alkyl, optionally substituted straight, branched or cyclic C₁₋₂₀ alkoxy, optionally substituted C₆₋₂₀ aryl, optionally substituted C₆₋₂₀ aryloxy, —OH, —CN, —NR₂₀R₂₁—COOH, COOR₂₀, —CONH₂—CONR₂₀R₂₁ and —CF₃, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN, —NR₃₀R₃₁, —COOR₃₀, —CONR₃₀R₃₁ and —CF₃; or R₁ and R₂, R₂ and R₃, and R₄ or R₄ and R₅ together form an aromatic ring composed of 6 to 10 carbon atoms which is optionally substituted with one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃, R₆, R₇, R₈ and R₉ are each independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C₁₋₂₀ alkyl, optionally substituted straight, branched or cyclic C₁₋₂₀ alkoxy, optionally substituted C₆₋₂₀ aryl and optionally substituted C₆₋₂₀ aryloxy wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃, or R₆ and R₇ together with the carbon atom to which they are bound and/or R₈ and R₉ together with the carbon atom to which they are bound form an optionally substituted C₃₋₂₀ cycloalkyl or an optionally substituted C₂₋₂₀ cycloalkoxy, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃, or one of R₆ and R₇ and one of R₈ and R₉ together form an optionally substituted C₅₋₁₀ cycloalkyl or an optionally substituted C₅₋₁₀ cycloalkoxy, wherein the substituents are independently selected from the group consisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃; R₁₀ is an optionally substituted straight, branched or cyclic C₁₋₁₀ alkyl, an optionally substituted C₆₋₁₀ aryl or —NR₁₁R₁₂ wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₁₀ alkyl, straight, branched or cyclic C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, -Hal, —OH, —ON, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃; provided that R₁₀ is not a tolyl group; R₁₁ and R₁₂ are independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C₁₋₁₀ alkyl and optionally substituted C₆₋₁₀ aryl, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₁₀ alkyl groups, straight, branched or cyclic C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, —OH, —ON, —NR₂₀R₂₁, —COOR₂₀, —CONR₂₀R₂₁ and —CF₃, or R₁₁ and R₁₂ together with the nitrogen atom to which they are bound form an optionally substituted C₂₋₁₀ cycloalkylamino group wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₁₀ alkyl, straight, branched or cyclic C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, —OH, —CN, —NR₂₀R₂₁, —COOR₂₃, —CONR₂₀R₂₁ and —CF₃; R₂₀ and R₂₁ are independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C₁₋₂₀ alkyl, optionally substituted straight, branched or cyclic C₁₋₂₀ alkoxy, optionally substituted C₆₋₂₀ aryl, optionally substituted C₆₋₂₀ aryloxy, —OH, —CN, —NR₃₀R₃₁, —COOR30, —CONR₃₀R₃₁ and —CF₃, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN and —CF₃; R₃₀ and R₃₁ are independently selected from the group consisting of hydrogen, optionally substituted straight, branched or cyclic C₁₋₂₀ alkyl, optionally substituted straight, branched or cyclic C₁₋₂₀ alkoxy, optionally substituted C₆₋₂₀ aryl, optionally substituted C₆₋₂₀ aryloxy, —OH, —CN and —CF₃, wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN and —CF₃; A is an optionally substituted straight- or branched-chain C₂₋₅ alkyl wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₁₀ alkyl, straight, branched or cyclic C₁₋₁₀ alkoxy, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy, or A is a group of formula (II):

wherein p is an integer selected from 1, 2, 3 or 4; each R₄₀ is independently selected from the group consisting of straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN and —CF₃; q and r are independently integers selected from 0, 1, 2 or 3 wherein q+r=1, 2 or 3; each R₄₁ is independently selected from the group consisting of hydrogen, straight, branched or cyclic C₁₋₂₀ alkyl, straight, branched or cyclic C₁₋₂₀ alkoxy, C₆₋₂₀ aryl, C₆₋₂₀ aryloxy, —OH, —CN and —CF₃; and Hal is a chlorine, bromine or iodine.
 21. The complex according to claim 20, wherein R₁, R₂, R₃, R₄ and R₅ are each independently selected from the group consisting of hydrogen, straight-chain C₁₋₁₀ alkyl and branched-chain C₁₋₁₀ alkyl.
 22. The complex according to claim 21, wherein R₁, R₂, R₃, R₄ and R₅ are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, propyl, n-butyl, i-butyl, s-butyl and t-butyl.
 23. The complex according to claim 22, wherein R₁, R₂, R₃, R₄ and R₅, are each hydrogen.
 24. The complex according to claim 20, wherein R₆, R₇, R₈ and R₉ are each independently selected from the group consisting of hydrogen and optionally substituted C₆₋₁₀, aryl.
 25. The complex according to claim 39, wherein R₆, R₇, R₈ and R₉ are each independently selected from the group consisting of hydrogen and phenyl.
 26. The complex according to claim 40, wherein one of R₆ and R₇ is phenyl and the other of R₆ and R₇ is hydrogen.
 27. The complex according to claim 40, wherein one of R₈ and R₉ is phenyl and the other of R₈ and R₉ is hydrogen.
 28. The complex according to claim 40, wherein R₆, R₇, R₈ and R₉ are hydrogen.
 29. The complex according to claim 35, wherein R is an optionally substituted straight, branched or cyclic C₁₋₁₀ alkyl, an optionally substituted C₆₋₁₀ aryl wherein the substituents are selected from the group consisting of one or more straight, branched or cyclic C₁₋₁₀ alkyl, straight, branched or cyclic C₁₋₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, -Hal, or —CF₃.
 30. The complex according to claim 35, wherein is a straight- or branched-chain C₁₋₁₀ alkyl or a C₆₋₁₀ aryl optionally substituted with one or more straight- or branched-chain C₁₋₁₀ alkyl groups.
 31. The complex according to claim 45, wherein is a methyl, p-methoxyphenyl, p-chlorophenyl, trifluoromethyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, 4-tert-butylphenyl, pentamethylphenyl or 2-naphthyl group.
 32. The complex according to claim 35, wherein A is —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— or —(CH₂)₅—. 